Phosphoinositide (PI) hydrolysis appears to regulate three separate, but interrelated, temporal phenomena in beta cells of the islets of Langerhans. These include the regulation of second phase insulin secretion in response to various agonists including glucose and cholecystokinin (CCK), the induction of time dependent potentiation (TDP) in response to a variety of agonist including glucose and CCK, and the induction of time independent suppression (TDS) in response to chronic stimulation with high glucose or CCK. The deranged pattern of insulin secretion after the induction of TDS by CCK bears a striking resemblance to that noted in Type II diabetes. Particularly cant is the reduction in first phase insulin secretion. Using isolated islets and isolated beta cells, the involvement of PI-derived second messenger molecules (inositol phosphates, diacylglycerol) and PI-dependent effector systems (C- kinase activity and spatial distribution) on these three insulin secretory response patterns will be assessed. Because our previous studies indicate that the second messenger molecule cAMP regulates the quantitative impact of various agonists on PI hydrolysis, studies will also be conducted to assess the possible ameliorating influence of this nucleotide on TDS of secretion induced by high glucose alone or low glucose plus CCK. Our hypothesis is that the same biochemical and metabolic pathways which regulate beta cell activation (in terms of insulin output) to various agonists also play a pivotal role in the development of aberrant patterns of insulin secretion which develop after chronic stimulation. Biochemical events activated by or associated with cellular increases in PI hydrolysis are implicated in these processes and our goal is to explore these interrelationships.